The control of human globin gene expression in erythroid cells involves trans-factors (substances active at multiple locations in the genome), which have yet to be identified or clearly described. One experimental approach to their identification is to study the effects on globin gene expression of well-described trans-factors from tumor viruses. Trans-factors from adenovirus 5 and pseudorabies virus are known to stimulate beta-globin transcription. HTLV-I specifies a similar trans-factor, tat 1, whose effect on non-viral genes is not known. We have designed three lines of transfection experiments to test the interaction of tat 1 and globin genes: (1) a normally inactive beta-globin plasmid is transfected into C81-66-45 cells, which produce tat 1. Detection of beta-globin RNA would suggest trans-activation of this gene by tat 1. (2) nonerythroid cells are cotransfected by a tat 1 expression vector and a beta-globin plasmid. Expression of beta-globin RNA only in the presence of tat 1 would prove trans-activation. (3) transfection of erythroid cells by the tat 1 expression vector will allow study of trans-activation of globin genes within the milieu of the intact erythroid cell. Other regulatory factors, such as chromatin structure, methylation, and the actual erythroid trans-factors will thus be in a normal state. If the initial experiments demonstrate trans-activation, more detailed questions will be asked, such as which DNA sequences are involved in the interaction and whether trans-factors activate or repress particular genes. The ultimate goal is to facilitate identification of the factors regulating globin expression in normal erythroid cells.